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Antimalarial treatment and malaria transmission: insights from the field

Jul 03, 2015

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Antimalarial treatment and malaria transmission: insights from the field - Conférence de la 8e édition du Cours international « Atelier Paludisme » - DJIMDE Abdoulaye - Mali - [email protected]

  • 1. Antimalarial treatment andmalaria transmission:insights from the fieldAbdoulaye DJIMDE PharmD, PhDMalaria Research and Training CenterUniversity of Bamako, Mali1Atelier PaludismeInstitut Pasteur Antananarivo14 20 Mars 2011

2. 2 Drug Resistance Spread of drugresistanceMolecular BiologyGeneticsPKPharmacogenomicsImmunologyPolicyHost-Parasite-VectorTransmission 3. Outline1. Sulfadoxine-Pyrimethamine (SP) andmalaria transmission in the field2. Impact of SP on P. falciparumgametocytes infectivity in vitro3. Artemisinin-based combinations andmalaria transmission in sub-Saharan AfricaConclusion3 4. P. falciparum life cycle 5. Current malaria control tools Artemisinin-based combination therapies (ACTs) Sulfadoxine-pyrimethamine recommended for IPT inpregnant women contemplated for IPTi and IPTc Quinine for severe malaria Insecticide treated nets & indoor residual spray 6. Sulfadoxine-Pyrimethamine treatmentand malaria transmission in a setting ofhigh Sulfadoxine-Pyrimethamine efficacyof Mali 7. Background Chloroquine efficacy decreasing Need alternative second line drug Prospective in vivo tests of CQ,amodiaquine and SP7 8. Study site Kolle: rural village; 2,500people 55 Km South of Bamako P. falciparum malariaendemic and seasonal Parasitemia: 40-50% dry season(October-April) 70-85% rainy season(May-September). Kolle 9. Study design Open randomized drug efficacy trial Children 6 months 5 years Three arms: Chloroquine, Amodiaquine, SP 28 days of follow up In vivo, in vitro, molecular andpharmacokinetic studiesMIM Antimalarial Drug Resistance Network 10. In vivo SP resistance in Mali 11. 11Evolution of gametocyte carriage after SPtreatmentBeavogui et al., IJP 2010 12. Molecular markers of SP resistanceAdapted from P. Wang et al. :Molecular and Biochemical Parasitology 89 (1997)161177 13. 13Mutations in pre-treatment asexualvs. post-treatment gametocytes0102030405060708090100%DHFR108DHFR59DHFR51DHPS437FRTripleQuadrupleAsexualGameto**** * p decreased infectivity SP also kills vector A. stephensi35 36. Artemisinine-based combinationtherapies and Malaria transmissionin the field 37. ACTs and malaria transmission A single intramuscular injection of 5 mg/kg artemisinin (togametocytemic rhesus monkeys) resulted in complete loss ofmosquito infectivity within 24 h of drug administration DuttaGP, et al. 1989 artemisinin derivatives reduced gametocyte carriage 18.5 foldand were found to reduce the transmission potential offalciparum malaria Price RN et al.,1996 Artemesinin-based combination therapies (ACT) forfalciparum malaria reduce gametocyte carriage, and thereforereduce transmission.37 38. ACTs and malaria transmission (2) NASBA study in Kenya data suggest that the potential ofmalaria transmission remains high even after treatmentwith artemisinin combination therapy Schneider P. et al,IJP, 2006 An efficacious antimalarial regimen with no specificgametocytocidal properties but a long prophylactic timewas estimated to be more effective at reducingtransmission than a short-acting ACT in the highest-transmission setting. Okell LC, PLoS Med, 200838 39. ObjectiveMeasure the impact of AS/AQ, AS/SPand AR-L on malaria transmission. 40. Day 28 Efficacynon-Corrected vs. PCR Corrected** P < 0.05 41. 41Evolution of gametocyte carriage by treatment arm onfollow up days 42. 42How infectious are the post-ACTgametocytes? 43. 43Methods Drug efficacy study Screening for gametocyte carriers Detect molecular markers of drug resistance Include gametocyte carriers aged 6 18 y. Direct feed starved F1 generation An. gambiae Maintain mosquitoes in lab for 8 days Presence and number of oocysts measured by dissection Compare the infectivity of pre-treatment vs. post-SPgametocytes to Anopheles gambiae Protocol approved by Ethics Committee of FMPOS 44. Study site Bougoula-Hameau: peri-urban village; 5000 people~400 Km South of Bamako P. falciparum malariahyper endemic No Insectaries around!! 45. Bougoula-Hameau, Sikasso, Mali45 46. 46 47. 47 48. 48 49. 49Direct feeding 50. 50 51. 51Comparing Ctrl vs. all post-ttt Oocyst positive051015202530354045 CtrlASSPASAQARLTreatment armsOocyst +******NS 52. 52Summary 3 ACTs decreased gametocyte carriageHOWEVER Would all ACTs reduce malaria transmission inhigh transmission settings? 53. Discussion Overall, infectivity was about three-times higher fordirect feeding than for membrane feeding (p < 0.001)Diallo M., et al Malaria Journal 2008 MFA Blood cells were separated from plasma bycentrifugation and plasma was replaced by a similarvolume of normal human plasma known to sustain malariatransmission. This step was performed to avoid thepossible interference (blocking or enhancing) antibodies togametocytes in the donors plasma.53 54. Conclusions Malaria eradication/elimination will requirenew, safe and truely gametocytocidal drug Need more sensitive gametocyte assays thatcould indicate gametocyte viability inaddition to prevalence and density. Field oriented studies need to be as close aspossible to natural conditions. Too muchcleaning of experimental design may yieldnice results but with little relevance to reallife. 54 55. Acknowledgements MRTC Study sites &participants Pr. Doumbo O &MRTC staff Nijmegen Adrian Luty Robert Sauerwein Support Government of Mali MIM/TDR NIAID/NIH FIC/NIH Ministre Franais dela Recherche (Pal +) Sanofi-Aventis55

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